IGFS AND OLIGODENDROCYTE DEVELOPMENT

关于少突胶质细胞发育的信息少得惊人 在正常发育的人脑中。尽管知识体系 根据在动物模型中进行的工作， 这些观察结果与人类少突胶质细胞发育的关系仍然是 无人回应此外，该序列在人类中特异性的阐明， 大脑将提供洞察产前和新生儿之间的关系 这一过程的干扰和获得性和dysgenetic 在人类婴儿中观察到的大脑异常。 本研究拟评估的假设为：1）。一 围产期人脑中的祖细胞对环境线索的反应， 成为一个成熟的少突胶质细胞， 大脑发育时间; 2.）胰岛素样生长因子（IGF-1， IGF-2）帮助指导人类少突胶质细胞的自分泌分化 或旁分泌方式;以及3.）IGFs在终末起调节作用， 涉及程序性细胞死亡人少突胶质细胞发育的步骤 （凋亡）。 为了验证这些假设，我们将确定人类 在组织培养物中的少突胶质细胞分化序列，所述组织培养物从 应用免疫组织化学技术检测人胎脑 少突胶质细胞成熟的特异性细胞标志物。来源和 IGF-1和IGF-2对少突胶质细胞分化的影响将被 用RNA技术，包括北方印迹、S1核酸酶 杂交和反义寡核苷酸翻译阻断。 最后，IGFs在新生人类细胞凋亡中的作用 将在体外研究少突胶质细胞群体，在 染色体完整性、转录、翻译和细胞形态。 这些研究将提供有关人类的重要信息。 来自人脑的少突胶质细胞分化， 关于这一过程的干扰如何可能导致的调查 在人类先天性和后天性白色病变中发现 婴儿。

Astonishingly little information exists about oligodendrocyte development in the normally developing human brain. Despite the body of knowledge assembled from work conducted in animal models, the primary question of how these observations relate to human oligodendrocyte development remains unanswered. Further, elucidation of this sequence specifically in human brain will provide insight into the relation between prenatal and neonatal disturbances of this process and both acquired and dysgenetic abnormalities of brain observed in the human infant. The hypotheses to be evaluated by the proposed research are: 1.) a progenitor cell in perinatal human brain responds to environmental cues to become a mature oligodendrocyte which first appears at a characteristic time in brain development; 2.) the insulin-like growth factors (IGF-1, IGF-2) help direct human oligodendroglial differentiation in an autocrine or paracrine manner; and 3.) the IGFs play a regulating role in a terminal step of human oligodendroglial development involving programmed cell death (apoptosis). To test these hypotheses, we will identify the human oligodendrocyte differentiation sequence in tissue culture obtained from human fetal brain by employing immunohistochemical techniques to detect specific cell markers of oligodendroglial maturation. The sources and effects of IGF-1 and -2 upon oligodendrocyte differentiation will be discerned with RNA techniques, including northern blot, S1 nuclease hybridization and anti-sense oligonucleotide translation blocking. Finally, the role of the IGFs in apoptosis of the nascent human oligodendrocyte population will be investigated in vitro,at the levels of chromosomal integrity, transcription, translation and cell morphology. These studies will provide crucial information about human oligodendroglial differentiation from human brain which will permit direct inquiry to be made concerning how disturbances of this process can result in congenital and acquired lesion of white matter found in the human infant.